rs199899258
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP2
The NM_005529.7(HSPG2):c.12520C>T(p.Arg4174Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,530 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R4174H) has been classified as Uncertain significance.
Frequency
Consequence
NM_005529.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HSPG2 | NM_005529.7 | c.12520C>T | p.Arg4174Cys | missense_variant | 90/97 | ENST00000374695.8 | NP_005520.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HSPG2 | ENST00000374695.8 | c.12520C>T | p.Arg4174Cys | missense_variant | 90/97 | 1 | NM_005529.7 | ENSP00000363827.3 | ||
HSPG2 | ENST00000486901.1 | n.1859C>T | non_coding_transcript_exon_variant | 4/11 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000151 AC: 23AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000361 AC: 9AN: 249626Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135356
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461318Hom.: 1 Cov.: 35 AF XY: 0.0000303 AC XY: 22AN XY: 726946
GnomAD4 genome AF: 0.000151 AC: 23AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 18, 2022 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 4174 of the HSPG2 protein (p.Arg4174Cys). This variant is present in population databases (rs199899258, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HSPG2-related conditions. ClinVar contains an entry for this variant (Variation ID: 585982). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 16, 2021 | - - |
Schwartz-Jampel syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 15, 2018 | The heterozygous p.Arg4174Cys variant in HSPG2 was identified in the compound heterozygous state by our study, with a pathogenic variant, in one individual with Schwartz-Jampel Syndrome. This variant has been identified in 0.0251% (6/23902) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs199899258). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools do not provide strong support for or against an impact to the protein. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the p.Arg4174Cys variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at